Thymidylate synthase prompts metastatic progression through the dTMP associated EMT process in pancreatic ductal adenocarcinoma
Thymidylate synthase prompts metastatic progression through the dTMP associated EMT process in pancreatic ductal adenocarcinoma
复制标题
胸苷酸合酶通过 dTMP 相关的胰腺导管腺癌 EMT 过程促进转移进展。
DOI：
10.1016/j.canlet.2018.01.026
复制
发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Wu, Yulian
中科院分区：
文献类型：
--
作者：
Kang, Muxing;Zheng, Wen;Wu, Yulian
胸苷酸合成酶（TS）是一种重要的代谢酶，抗TS策略已被证明是治疗癌症的有效方法。然而，TS在胰腺导管腺癌（PDA）中的真正作用仍然存在争议。我们系统地评估了TS的预后价值以及TS是否与PDA的恶性进展相关。检测PDA整体标本中TS蛋白和mRNA的表达水平，首次明确TS在胞浆和胞核中表达对预后的影响。在体外试验中评估TS对肿瘤细胞行为的影响，并在两种不同的PDA转移模型中进一步确定TS相关的转移潜力。回顾性临床分析首次发现肿瘤细胞核TS表达与PDA患者淋巴结转移呈正相关，与总生存期呈负相关。随后的实验进一步证实，TS去除能有效抑制体外EMT（epithelial to mesenchymal）过程，并在两种不同的PDA小鼠模型中降低大部分转移灶，而dNTP池失衡导致的dTMP生物合成障碍可能是其根本原因。总的来说，本研究提出了联合抗TS方案治疗转移性PDA的前瞻性策略，我们强烈建议进一步的临床标准化研究，以验证TS在PDA中的预后价值和治疗潜力。(C)2018爱思唯尔B.V.保留所有权利。
As a fundamental metabolic enzyme, anti-Thymidylate synthase (TS) strategy has been shown to be an effective therapy for human cancers. However, the genuine effects of TS in pancreatic ductal adenocarcinoma (PDA) are still conflicting. We systemically assessed the prognostic value and whether TS associated with malignant progression in PDA. Protein and mRNA expression level of TS were evaluated in en bloc PDA samples, the prognostic effect of TS expressed in cytoplasm or cytonuclear was determined separately in the first time. The impact of TS on tumor cell behaviors was assessed in in vitro assays, and the TS associated metastatic potential was further determined in two different PDA metastatic models. The retrospective clinical analysis firstly demonstrated that tumor cytonuclear TS expression was positively correlated with lymphatic metastasis and negatively correlated with the overall survival (OS) in PDA patients. The subsequent experiments further confirmed that TS depletion can effectively abate EMT (epithelial to mesenchymal) process in in vitro and decline most of the metastatic lesions in two different PDA mice models, and the deoxythymidine monophosphate (dTMP) biosynthesis malfunction resulted imbalanced dNTP pools may be the fundamental causation. Collectively, the present study suggested the prospective strategy of combined anti-TS scheme for metastatic PDA, and we strongly suggest further clinical standardization research with a large cohort to verify the prognostic value and the therapeutic potential of TS in PDA. (C) 2018 Elsevier B.V. All rights reserved.